Alzheimer's Disease (AD) begins with synaptic and dendritic spine pathology that manifests as memory, learning and behavioral deficits. As disease progresses, phospho-tau (p-tau), paired helical filaments (PHFs) and neurofibrillary tangles (NFTs) appear, causing neurodegeneration. Murine models that exclusively overproduce A?42, while showing synaptic pathology, alterations in plasticity and behavior, plaques and neuro-inflammation, fail to develop tauopathy or neurodegeneration. Conversely, mice expressing tau-mutants exclusively develop synaptic disease, tauopathy and neurodegeneration in the absence of excess A?42. This application addresses how soluble, multimeric A?42 induces tauopathy and neurodegeneration, a critical gap in our knowledge. We show that Pin1, a peptidyl-prolyl isomerase previously implicated in both amyloid precursor processing (APP) and p-tau accumulation, can be suppressed by A?42 or repeat-domain tau signaling. Loss of Pin1 activity led to acute dendritic spine and synapse loss which could be prevented by the calcineurin inhibitor, FK506. Pin1 KO in adult murine brain, in addition to causing rapid synaptic and dendritic spine loss, led to p-tau accumulation and neurodegeneration. Thus, we hypothesize that in AD, progressive Pin1 inactivation by A?42 and tau signaling leads to several of the major AD pathologies including synaptic disease, tauopathy and neurodegeneration. To characterize the mechanism for these novel findings, we propose to 1). Determine how signaling induced by AP42 or tau regulates Pin1 activity and leads to spine loss and neurodegeneration and 2). Determine if FK506 or exogenous Pin1 can preserve Pin1 activity to attenuate or prevent pathology in AD model mice. Successful completion of these studies will reveal important aspects of Ca2+ signaling in spines, expand our knowledge of the regulation and function of Pin1 in the brain, improve our understanding of a critical feature of AD pathogenesis and provide support for a clinical trial of low-dose FK506 in MCI patients.